Cancer is a major cause of morbidity and mortality throughout the world and in spite of recent advances in molecular pathogenesis of cancer, it still remains an enigmatic disease. It is estimated that there were more than 1.2 million new cases of cancer (excluding nonmelanoma skin cancers and carcinoma in situ of cervix), and 564000 deaths from cancer in 1998 in the United States. Now it is becoming increasingly clear that cancer is an extraordinarily diverse disease caused not only by chemicals but also by bacteria, viruses, parasites, metals and hormones. Cancer causing agents can be classified as direct and indirect carcinogens. Direct (genotoxic) carcinogens induce tumors by altering the genetic information of cells, (chemicals and radiation through DNA damage resulting in somatic mutations and the presence of transforming genes as in some viruses), whereas indirect (nongenotoxic) carcinogens induce tumors through a variety of biological effects. Peroxisome proliferators are a diverse group of synthetic and naturally occurring compounds that are of therapeutic, industrial and agricultural value. We discovered the liver tumor inducing properties of this diverse class of important chemicals and showed that they are nongenotoxic. We hypothesize that oxygen free radicals produced by peroxisome proliferator activated receptor alpha (PPARalpha) mediated increases in peroxisomal fatty acid beta-oxidation and other hydrogen peroxide generating enzymes will lead to DNA damage and increased cell proliferation resulting in hepatocarcinogenesis. To fully evaluate the role of oxidative stress and cell proliferation in peroxisome proliferator-induced hepatocarcinogenesis we will utilize mice deficient in fatty acyl-CoA oxidase (AOX), deficient in PPARalpha and deficient in both AOX and PPARalpha. The specific aims include: 1) analysis of hepatocarcinogenesis in AOX null mice by examining the effect of natural activators of PPARalpha and critically evaluating the role of apoptosis and cell proliferation; 2) assess the role of sustained activation of PPARalpha and steatohepatitis in the development of liver tumors in AOX null mice by ascertaining the tumor chemopreventive potential of nonsteroidal antiinflammatory agents; 3) examine the role of PPARalpha and AOX in peroxisome proliferator induced pleiotropic responses by studying (PPARalpha) and AOX double null mice; 4) critical analysis of the role of oxidative stress in hepatocarcinogenesis induced by steatohepatitis resulting from deficiency of dietary factors, and 5) evaluation of the role of growth factors and cell cycle proteins in hepatocarcinogenesis induced by dietary factors and ciprofibrate in rats and spontaneous tumors in AOX null mice. The anticipation is that elucidation of mechanistic aspects of hepatocarcinogenesis induced by peroxisome proliferators, the prototype of nongenotoxic carcinogens, will not only enable the identification of factors responsible for a large majority of human tumors, usually referred to as 'spontaneous tumors' but also help to develop new therapeutic strategies.